Molecular Genetics of Pompe Disease: a Comprehensive Overview

Overview

Journal Ann Transl Med

Publisher AME Publishing Company

Date 2019 Aug 9

PMID 31392190

Citations 36

Authors

Paolo Peruzzo

Eleonora Pavan

Andrea Dardis

Affiliations

Soon will be listed here.

Abstract

Pompe disease (PD) is an autosomal recessive lysosomal disorder caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme due to mutations in the gene. The enzymatic deficiency leads to the accumulation of glycogen within the lysosomes. Clinically, the disease has been classically classified in infantile and childhood/adult forms. The gene has been localized to chromosome 17q25.2-q25.3 and to date, 582 mutations distributed throughout the whole gene have been reported (HGMD: http://www.hgmd.cf.ac.uk/ac/). All types of mutations have been described; missense variants are the most frequent type followed by small deletions. Most mutations are private or found in a small number of families. However, an exception is represented by the c.-32-13T>G splice mutation that is very common in patients of Caucasian origin affected by the childhood/adult form of the disease, with an allelic frequency ranging from 40% to 70%. In this article, we review the spectrum of mutations, their distribution in different populations, and their classification according to their impact on splicing process, protein expression and activity. In addition, whenever possible, we discuss the phenotype/genotype correlation. The information collected in this review provides an overview of the molecular genetics of PD and can be used to facilitate diagnosis and genetic counseling of families affected by this disorder.

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References

van der Wal E, Bergsma A, Pijnenburg J, van der Ploeg A, Pijnappel W . Antisense Oligonucleotides Promote Exon Inclusion and Correct the Common c.-32-13T>G GAA Splicing Variant in Pompe Disease. Mol Ther Nucleic Acids. 2017; 7:90-100. PMC: 5415969. DOI: 10.1016/j.omtn.2017.03.001. View

Kishnani P, Hwu W, Mandel H, Nicolino M, Yong F, Corzo D . A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr. 2006; 148(5):671-676. DOI: 10.1016/j.jpeds.2005.11.033. View

McCready M, Carson N, Chakraborty P, Clarke J, Callahan J, Skomorowski M . Development of a clinical assay for detection of GAA mutations and characterization of the GAA mutation spectrum in a Canadian cohort of individuals with glycogen storage disease, type II. Mol Genet Metab. 2007; 92(4):325-35. DOI: 10.1016/j.ymgme.2007.07.006. View

Palmer R, Amartino H, Niizawa G, Blanco M, Pomponio R, Chamoles N . Pompe disease (glycogen storage disease type II) in Argentineans: clinical manifestations and identification of 9 novel mutations. Neuromuscul Disord. 2006; 17(1):16-22. DOI: 10.1016/j.nmd.2006.09.004. View

Kroos M, Pomponio R, Van Vliet L, Palmer R, Phipps M, van der Helm R . Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. Hum Mutat. 2008; 29(6):E13-26. DOI: 10.1002/humu.20745. View

Semplicini C, Letard P, Antonio M, Taouagh N, Perniconi B, Bouhour F . Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study. J Inherit Metab Dis. 2018; 41(6):937-946. DOI: 10.1007/s10545-018-0243-7. View

Huie M, Chen A, Tsujino S, Shanske S, DiMauro S, Engel A . Aberrant splicing in adult onset glycogen storage disease type II (GSDII): molecular identification of an IVS1 (-13T-->G) mutation in a majority of patients and a novel IVS10 (+1GT-->CT) mutation. Hum Mol Genet. 1994; 3(12):2231-6. DOI: 10.1093/hmg/3.12.2231. View

Grodecka L, Buratti E, Freiberger T . Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?. Int J Mol Sci. 2017; 18(8). PMC: 5578058. DOI: 10.3390/ijms18081668. View

Ausems M, ten Berg K, Sandkuijl L, Kroos M, Bardoel A, Roumelioti K . Dutch patients with glycogen storage disease type II show common ancestry for the 525delT and del exon 18 mutations. J Med Genet. 2001; 38(8):527-9. PMC: 1734921. DOI: 10.1136/jmg.38.8.527. View

10.

Scheidegger O, Leupold D, Sauter R, Findling O, Rosler K, Hundsberger T . 36-Months follow-up assessment after cessation and resuming of enzyme replacement therapy in late onset Pompe disease: data from the Swiss Pompe Registry. J Neurol. 2018; 265(12):2783-2788. DOI: 10.1007/s00415-018-9065-7. View

11.

Kroos M, Pomponio R, Hagemans M, Keulemans J, Phipps M, DeRiso M . Broad spectrum of Pompe disease in patients with the same c.-32-13T->G haplotype. Neurology. 2007; 68(2):110-5. DOI: 10.1212/01.wnl.0000252798.25690.76. View

12.

Joshi P, Glaser D, Schmidt S, Vorgerd M, Winterholler M, Eger K . Molecular diagnosis of German patients with late-onset glycogen storage disease type II. J Inherit Metab Dis. 2008; 31 Suppl 2:S261-5. DOI: 10.1007/s10545-008-0820-2. View

13.

Montalvo A, Bembi B, Donnarumma M, Filocamo M, Parenti G, Rossi M . Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II. Hum Mutat. 2006; 27(10):999-1006. DOI: 10.1002/humu.20374. View

14.

Hasilik A, Neufeld E . Biosynthesis of lysosomal enzymes in fibroblasts. Phosphorylation of mannose residues. J Biol Chem. 1980; 255(10):4946-50. View

15.

Becker J, Vlach J, Raben N, Nagaraju K, Adams E, Hermans M . The African origin of the common mutation in African American patients with glycogen-storage disease type II. Am J Hum Genet. 1998; 62(4):991-4. PMC: 1377028. DOI: 10.1086/301788. View

16.

Dardis A, Zanin I, Zampieri S, Stuani C, Pianta A, Romanello M . Functional characterization of the common c.-32-13T>G mutation of GAA gene: identification of potential therapeutic agents. Nucleic Acids Res. 2013; 42(2):1291-302. PMC: 3902950. DOI: 10.1093/nar/gkt987. View

17.

Parini R, De Lorenzo P, Dardis A, Burlina A, Cassio A, Cavarzere P . Long term clinical history of an Italian cohort of infantile onset Pompe disease treated with enzyme replacement therapy. Orphanet J Rare Dis. 2018; 13(1):32. PMC: 5806382. DOI: 10.1186/s13023-018-0771-0. View

18.

Huie M, Menaker M, McAlpine P, Hirschhorn R . Identification of an E689K substitution as the molecular basis of the human acid alpha-glucosidase type 4 allozyme (GAA*4). Ann Hum Genet. 1996; 60(5):365-8. DOI: 10.1111/j.1469-1809.1996.tb00433.x. View

19.

Liu X, Wang Z, Jin W, Lv H, Zhang W, Que C . Clinical and GAA gene mutation analysis in mainland Chinese patients with late-onset Pompe disease: identifying c.2238G > C as the most common mutation. BMC Med Genet. 2014; 15:141. PMC: 4411720. DOI: 10.1186/s12881-014-0141-2. View

20.

Ausems M, Verbiest J, Hermans M, Kroos M, Beemer F, Wokke J . Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet. 1999; 7(6):713-6. DOI: 10.1038/sj.ejhg.5200367. View